Psoriasis is a cutaneous autoimmune disease that affects as many as 125 million people worldwide. Current therapeutics for psoriasis include systemic acting immuno-suppressive drugs for which the long-term effects remain a concern. Psoriasis is a cell-mediated disease dependent on T helper (Th) 17 effector cells that are biased by cutaneous DCs. Importantly, the stimuli that induce DCs and keratinocytes to secrete Th polarizing cytokines, particularly in psoriasis, are complex and not completely understood. In this context, ATP is a particularly appealing alarmin that, via P2X7 receptor (P2X7R) signaling, induces NF-B activation and the IL- 23/IL-17 axis, both of which have been shown to be psoriasis susceptibility pathways. Thus, P2X7R signaling links early inflammatory triggers with psoriasis susceptibility factors. Interestingly, NF-B also leads to the maintenance of P2X7R expression forming a positive feedback mechanism. Results from our ongoing studies support a currently unappreciated role for P2X7R signaling in psoriasis pathogenesis. Specifically, we provide evidence that in healthy human skin, P2X7R signaling induces innate immunity, stimulates DCs to express IL- 1, IL-6, IL-23, IL-15, and VEGF, and promotes a Th17 bias. Additionally, P2X7R expression is increased in lesional and non-lesional skin of psoriatic patients compared to healthy donors. This increased P2X7R expression in non-lesional skin represents a primary abnormality in the skin of patients with psoriasis, rather than a secondary effect of inflammation. Supported by this theoretical and experimental rationale, we hypothesize that within a genetically susceptible microenvironment cutaneous P2X7R signaling is a mechanism of psoriasis pathogenesis that can be a target for therapeutics. Thus, our goal in this preclinical proposal is to determine the involvement of P2X7R signaling in the development and maintenance of psoriatic lesions, and to elucidate novel P2X7R-dependent pathogenic mechanisms that can be exploited for novel psoriasis therapies. To test our novel and innovative hypothesis we have established the following specific aims: Aim 1 will define the inflammatory pathways induced by cutaneous P2X7R signaling. Aim 2 will establish the involvement of P2X7R signaling in psoriasis pathogenesis within a genetically susceptible microenvironment, and Aim 3 will examine the therapeutic capacity of P2X7R antagonist to diminish psoriatic lesions. The conserved nature of ATP and P2X7R signaling pathways in mice and humans supports the translational value of the studies we propose and provide an opportunity to utilize a unique and innovative approach by combing both human and murine models of psoriasis. At the conclusion of this proposal we will have determined that P2X7R signaling is pathogenic in genetically susceptible psoriatic microenvironments. Our results will lead to an increased scientific knowledge base, the development of a model to further examine P2X7R signaling mechanisms and psoriasis pathogenesis, and proof-of-principle studies for new therapeutic strategies for future proposals.